Injection of F1 hybrid mice with either murine cytomegalovirus (MCMV) or parental spleen cells (graft-versus-host reaction - GVHR) results in rapid and severe immunosuppression. Inoculation of either the virus or parental cells were selected so that they would be below the threshold for severe immunosuppression. However, when these two inocula were combined, severe immunosuppression was observed. Futhermore, injection of F1 mice with parental lymphocytes that recognize only class I MHC determinants does not result in immune suppression. However, a combination of class I recognition and MCMV infection results in profound immune suppression. Infection of host mice with MCMV prior to induction of GVH resulted in augmented immune suppression, whereas infection of donor mice with MCMV before induction of GVH resulted in reduced immune suppresion. The combination of MCMV and GVHR also resulted in interstitial pneumonitis, whereas either insult alone had no detectable pathogenic effect on the lungs. These studies permit the investigation of the immunosuppression of MCMV infection and the possibility consequences of CMV infection coupled with a GVHR. Mice were treated in vivo in such a way to render them deficient in L3T4+ or both L3T4+ and Lyt2+ T cells, and then infected with MCMV. Mice infected with MCMV after L3T4 depletion survived, whereas mice infected after depletion of both L3T4+ and Lyt2+ cells died. This observation may be relevant for determining the T cell subsets important for protection against CMV infection.